2-Deoxystreptamine derivatives, pharmaceutical compositions thereof and therapeutic methods using same

This invention provides a compound having the formula: ##STR1## wherein R.sup.1 and R.sup.3 independently are hydrogen, --CHO, --COCH.sub.3, --COR.sup.7, --A--Ar--(Q).sub.z, etc.; wherein D is a C.sub.1-6 linear, C.sub.3-8 branched or cyclic group having from 4 to about 15 atoms, consisting of C, etc.; wherein D is unsubstituted or substituted with one or more groups independently selected from the group consisting of --OH, NH.sub.2, --NHR.sub.7, etc.; wherein each Q is independently --CNH(NHY), --NHCNH(NHY), --SO.sub.2 W, --SOW, etc.; wherein Y is hydrogen, alkyl, alkenyl, --B--NH.sub.2, --B--NHR.sup.8, etc.; wherein W is alkyl, alkenyl, --B--NH.sub.2, etc.; wherein A nd B independently are a bond, or a C.sub.1-6 linear, C.sub.3-8 branched or cyclic linking group having from 1 to about 15 atoms, consisting of C, optionally interrupted by N, S, P and O; wherein A and B independently are unsubstituted or substituted with --OH, NH.sub.2, etc.; wherein R.sup.7 is an alkyl, a branched alkyl, etc.; wherein R.sup.8, R.sup.9, and R.sup.10 are independently represented by hydrogen, alkyl, branched alkyl, etc.; wherein x is 0, 1 or 2; and z is 0, 1, 2, or 4; wherein R.sup.1 ' and R.sup.3 ' are independently selected from the group consisting of hydrogen, alkyl and benzyl, or alternatively, R.sup.1 and R.sup.1 ' or R.sup.3 and R.sup.3 ' with their respective nitrogen atoms independently form a phthalimido, succinimido, etc.; wherein R.sup.4, R.sup.5, and R.sup.6 independently are selected from the group consisting of hydrogen, --CHO, --COCH.sub.3, --COR.sup.7, etc.; therein said saccharides are optionally linked at the one position of said saccharid group; wherein R.sup.4 and R.sup.5, or R.sup.5 and R.sup.6, together comprise a methylidene, ethylidene, isopropylident, cyclohexylidene or benzylidene bridge, or R.sup.3 and R.sup.4, or R.sup.1 and R.sup.6, together independently form an intramolecular carbamate; wherein R.sup.5 is not hydrogen or glycosyl when R.sup.3 and R.sup.4, or R.sup.1 and R.sup.6, together independently form an intramolecular carbamate; with the provisio that at least two of R.sup.1, R.sup.1 ', R.sup.3, R.sup.3 ', R.sup.4, R.sup.5, and R.sup.6 are not hydrogen. Also provided are pharmaceutical compositions comprising the compound and methods of inhibiting binding of human immunodeficiency virus REV protein to RRE.

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Claims

1. A compound having the formula: ##STR41## wherein R.sup.1 and R.sup.3 independently are hydrogen, --CHO, --COCH.sub.3, --COR.sup.7, --COCCl.sub.3, --COCF.sub.3, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, a d or l amino acid, --D--(Q).sub.x or --A--Ar--(Q).sub.z;

wherein D is a C.sub.1-6 linear alkvl, C.sub.3-8 branched alkvl or C.sub.3-6 cycloalkyl, consisting of C with the proviso that D is optionally interrupted by at least one atom independently selected from the group consisting of N, S, P and O;
wherein D is unsubstituted or substituted with one or more groups independently selected from the group consisting of --OH, NH.sub.2, --NHR.sup.7, --NHR.sup.7 R.sup.8, and alkyl;
wherein each Q is independently --CNH(NHY), --NHCNH(NHY), --NHCO(NHY), --CONHY, --COOH, --COOY, --NHCOY, --NHSO.sub.2 Y, halogen, --CN, --SO.sub.2 W, --SOW --OPO.sub.3, imidazolyl, thiazolyl, pyridyl or indolyl;
wherein Y is hydrogen, alkyl, alkenyl, --B--NH.sub.2, --B--NHR.sup.8, --B--NR.sup.8 R.sup.9, --B-aryl, --B-substituted aryl, --B-morpholino or --B-pyridyl;
wherein W is alkyl, alkenyl, --B--NH.sub.2, --B--NHR.sup.8, --B--NR.sup.8 R.sup.9, --B-aryl, --B-substituted aryl, --B-morpholino or --B-pyridyl;
wherein A and B independently are a bond, or a C.sub.1-6 linear alkyl, C.sub.3-8 branched alkyl or C.sub.3-6 cycloalkyl, consisting of C, with the proviso that A and B are optionally interrupted by at least one atom independently selected from the group consisting of N, S, P and O;
wherein A and B independently are unsubstituted or substituted with one or more groups independently selected from the group consisting of --OH, NH.sub.2, --NHR.sup.7, --NHR.sup.7 R.sup.8, and alkyl;
wherein Ar is an aryl or heteroaryl group having from 6-10 ring atoms and 1-2 rings;
wherein R.sup.7 is an alkyl, a branched alkyl, a cycloalkyl or an aryl group;
wherein R.sup.8, R.sup.9, and R.sup.10 are independently represented by hydrogen, alkyl, branched alkyl, cycloalkyl or aryl groups;
wherein x is 0, 1 or 2; and z is 0, 1, 2, 3 or 4;
wherein R.sup.1 ' and R.sup.3 ' are independently selected from the group consisting of benzyl or alternatively, R.sup.1 and R.sup.1 ' or R.sup.3 and R.sup.3 ' with their respective nitrogen atoms independently form a phthalimido, succinimido, 2,5-dimethylpyrrolo- or N-1,1,4,4-tetramethyldisilylazacyclopentane group;
wherein R.sup.4, R.sup.5, and R.sup.6 independently are selected from the group consisting of hydrogen, --CHO, --COCH.sub.3, --COR.sup.7, --COCCl.sub.3, --COCF.sub.3, a d or l amino acid compounds having a glycosyl group, --D--(Q).sub.x and --A--Ar--(Q).sub.z;
wherein said saccharides are optionally linked at the one position of said saccharide group;
wherein R.sup.4 and R.sup.5, or R.sup.5 and R.sup.6, together are a methylidene, ethylidene, isopropylidene, cyclohexylidene or benzylidene bridge, or R.sup.3 and R.sup.4, or R.sup.1 and R.sup.6, together independently form an intramolecular carbamate;
with the proviso that at least two of R.sup.1, R.sup.1 ', R.sup.3, R.sup.3 ', R.sup.4, R.sup.5, and R.sup.6 are not hydrogen.

2. The compound of claim 1 wherein R.sup.1 and R.sup.3 are independently A--Ar--(Q).sub.z having a structure selected from the group consisting of: ##STR42## and wherein each z is independently 0, 1 or 2.

3. The compound of claim 1 wherein R.sup.4, R.sup.5 and R.sup.6 are independently A--Ar--(Q).sub.z having a structure selected from the group consisting of: ##STR43## wherein each z is 0, 1 or 2.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition for inhibiting binding of human immunodeficiency virus REV protein to RRE in cells comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of inhibiting binding of human immunodeficiency virus REV protein to RRE in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

7. A method of inhibiting binding of human immunodeficiency virus REV protein to RRE in cells comprising administering a therapeutically effective amount of the compound of claim 1.

Referenced Cited
U.S. Patent Documents
3828021 August 1974 Beattie et al.
3872080 March 1975 Daniels
4218561 August 19, 1980 Paulsen
4396609 August 2, 1983 Daum et al.
5288514 February 22, 1994 Ellman
5496938 March 5, 1996 Gold et al.
5534408 July 9, 1996 Green et al.
5565324 October 15, 1996 Still et al.
Foreign Patent Documents
WO 94/09792 May 1994 WOX
Other references
  • Canas-Rodriguez et al., Carbohydrate Research, 68:43-53, 1979. Pandey et al., J. of Chromatography, 170:498-501, 1979. Zapp et al., Cell, 74:969-978, 1993. CA109: 231413, 1988. CA95: 25529, 1981. CA110: 113298, 1988. CA96: 14880, 1981. CA89: 215683, 1978. CA81: 13755, 1974. CA70: 58219, 1968. CA62: 2819, 1964.
Patent History
Patent number: 5942547
Type: Grant
Filed: Sep 6, 1996
Date of Patent: Aug 24, 1999
Assignee: Scriptgen Pharmaceuticals, Inc. (Waltham, MA)
Inventors: Gary R. Gustafson (Bedford, MA), David G. Powers (Maynard, MA), Mark A. Wuonola (Waltham, MA)
Primary Examiner: Yogendra N. Gupta
Law Firm: Darby & Darby
Application Number: 8/709,343
Classifications
Current U.S. Class: Plural Carboxamide Groups Or Plural C=o Groups Bonded Directly To The Same Nitrogen (514/616); O-glycoside (514/25); Two Or More Nitrogen Atoms Bonded Directly To The Cyclohexyl Ring (514/36); The Additional Hetero Ring Consists Of One Nitrogen And Four Carbons (e.g., Nicotine, Etc.) (514/343); Tricyclo Ring System Having The Five-membered Hetero Ring As One Of The Cyclos (514/411); The Hetero Ring Is Five-membered (514/461); Chalcogen Bonded Directly To The Hetero Ring (514/473); Benzene Ring Containing (514/637); Plural Pyridine Or Partially Hydrogenated Pyridine Rings (546/255); 546/2764; Plural Benzothiazoles (including Hydrogenated) (548/156); Chalcogen Bonded Directly To Ring Carbon Of The Thiazole Ring (548/157); Chalcogen Bonded Directly To Ring Carbon Of The Thiazole Ring (548/182); Nitrogen Bonded Directly To Ring Carbon Of The Oxazole Ring (548/233); 1,2,3-triazoles (including Hydrogenated) (548/255); 548/3054; 548/3351; 548/3411; Hydroxy, Bonded Directly To Carbon, Or Ether Containing (h Of -oh May Be Replaced By A Substituted Or Unsubstituted Ammonium Ion Or A Group Ia Or Iia Light Metal) (564/158); Acyclic (564/159); The Ether Oxygen Is Bonded Directly To The Aryl Ring Or Ring System (564/347); Alicyclic Ring Or Ring System, Having Plural Amino Nitrogens Attached Directly Or Indirectly Thereto By Acyclic Nonionic Bonding, Attached Indirectly To An Aryl Ring Or Ring System By Acyclic Nonionic Bonding (564/306)
International Classification: A61K 3116; C07C23300;